US2009035267A1PendingUtilityA1
Acyclic, pyridazinone-derived hepatitis c serine protease inhibitors
Est. expiryJul 31, 2027(~1 yrs left)· nominal 20-yr term from priority
A61P 43/00A61K 38/00C07K 5/0808A61P 31/12
41
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Claims
Abstract
The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof, which can inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
A is selected from the group consisting of —(C═O)—O—R 1 , —(C═O)—R 2 , —C(═O)—NR 1 R 2 , —S(O) 2 —R 1 , and —S(O) 2 —NR 1 R 2 ;
wherein, R 1 is independently selected at each occurrence from the following groups:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl; and
(vii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
wherein, R 2 is independently selected at each occurrence from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl; and
(viii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
L is selected from the following groups:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl; substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl; substituted —C 3 -C 12 cycloalkenyl; heterocyclic; or substituted heterocyclic; and
(ii) aryl; or substituted aryl;
Q is selected from the group consisting of:
(i) hydrogen;
(ii) SR 2 ; where R 2 is as previously defined; and
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; heterocyclic or substituted heterocyclic;
G is selected from —NHS(O) 2 —R 3 and —NH(SO 2 )NR 4 R 5 ;
wherein, R 3 is independently selected at each occurrence from the following groups:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl;
(vii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
wherein, R 4 and R 5 are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
X, Y, and Z are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ii) —CN;
(iii) —N 3 ;
(iv) halogen;
(v) OR 6 ;
(vi) NR 7 R 8 ;
(vii) aryl;
(viii) substituted aryl;
(ix) heteroaryl;
(x) substituted heteroaryl;
(xi) —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl;
(xii) —C 1 -C 6 alkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(xiii) —C 2 -C 6 alkenyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and
(xiv) —C 2 -C 6 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form a cyclic moiety, which is selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
wherein, R 6 is independently selected at each occurrence from the following groups:
(i) hydrogen
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
Wherein, R 7 and R 8 are independently selected at each occurrence from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
m=0, 1, or 2;
n=1, 2, or 3; and
s=0, 1, 2, or 3.
2 . The compound of claim 1 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof, where m, n, A, L, X, Y, Z, Q and G are as defined in claim 1 .
3 . A compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, which is selected from compounds of Formula III wherein A, Q′, G and L are delineated in table 1.
TABLE 1
III
Example
A
Q′
G
L
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
4 . A pharmaceutical composition comprising (1) a compound having a formula selected from formulae I, II, or III as described in the specification, or (2) a pharmaceutically acceptable salt, ester or prodrug of said compound.
5 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
6 . A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 5 .
7 . A method of inhibiting the replication of hepatitis C virus, the method comprising contacting a hepatitis C virus with an effective amount of a compound of claim 1 .
8 . A method of claim 7 further comprising administering concurrently an additional anti-hepatitis C virus agent.
9 . The method of claim 8 , wherein said additional anti-hepatitis C virus agent is selected from the group consisting of α-interferon, β-interferon, ribavarin, and adamantine.
10 . The method of claim 8 , wherein said additional anti-hepatitis C virus agent is an inhibitor of other targets in the hepatitis C virus life cycle which is selected from the group consisting of helicase, polymerase, metalloprotease, and IRES.
11 . A process of making a compound with a formula selected from Formulae I, II, or III according to a scheme, method or process described herein.
12 . The pharmaceutical composition of claim 4 , further comprising another anti-HCV agent.
13 . The pharmaceutical composition of claim 4 , further comprising an agent selected from interferon, ribavirin, amantadine, another HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal ribosome entry site inhibitor.
14 . The pharmaceutical composition of claim 4 , further comprising pegylated interferon.
15 . The pharmaceutical composition of claim 4 , further comprising another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator.Join the waitlist — get patent alerts
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